This ongoing project previously demonstrated linkage of type 2 diabetes (T2DM) to chromosome 1q21-q24 in Caucasians, and more recently in African American subjects. Data from the last funding period show convincingly that although replicating well across ethnic groups, the 1q linkage region encompasses multiple susceptibility loci, and that these loci interact with other chromosomal regions in Caucasians. Furthermore, data from our laboratory and others suggest that most susceptibility variants will be noncoding. Based on these findings, we propose several hypotheses. 1) Multiple 1q loci of varying effect size contribute to the linkage signal, and 2) at least some loci will be unique to each population. 3) These susceptibility variants will alter gene expression or noncoding RNA in key physiologic pathways, and 4) some subset of these loci can be detected by alteration of gene expression in available tissues (fat, lymphocytes, and muscle). 5) Chromosome 1 loci will interact with each other and with non-chromosome 1 susceptibility loci to increase T2DM susceptibility. We propose 5 aims to test these hypotheses. Our studies are designed to complement NIH funded international, high throughput efforts to localize 1q susceptibility loci by providing physiologic and lower throughput approaches for regions of significance in our populations. In Aims 1 and 2, we will use dense maps, allelic association, family studies, and intermediate trait studies to extend initial findings from our laboratory and the Consortium in Caucasian and African American samples. Aim 3 will test for interactions both among chromosome 1 loci and between the strongest 1q loci and regions on other chromosomes, particularly non-1 q loci with evidence for association in other populations. Aim 4 will use novel methods to test for allelic imbalance in broadly defined candidate genes, suggesting nearby cis-acting regulatory variants, in adipocytes, muscle, and transformed lymphocytes obtained from Caucasian and African American human subjects. Aim 5 will initiate studies to identify the physiologic consequences of the most strongly associated variants, including gene expression in adipocytes and muscle. Together with ongoing efforts from the Consortium and other laboratories, we expect these studies will localize and begin to characterize the specific variants that increase susceptibiltiy to T2DM in two populations, and will lead to additional studies to identify the biological pathways involved in T2DM pathogenesis.